Compounds of the cyclopentanopolyhydrophenanthrene series and process of making same



Patented Oct. 22, 1946 COMPOUNDS OF THE CYCLOPENTANOPOLY-HYDROPHENANTHRENE SERIES AND PROCESS OF MAKING SAME Tadeus Reichstein,Basel, Switzerland No Drawing. Application March 20, 1942, Serial No.435,570. In Switzerland March 21, 1941 sclaims. (o1. zoo-397.3)

It has been found that compounds of thecyclopentano-polyhydrophenanthrene series unsaturated in ring C can beobtained if compounds of theaetiocholane or pregnane series, which areunsaturated in the neucleus and contain in ring C in the ll-position afree or esterified hydroxyl group as substituent, are subjected to atreatment which eliminates this substituent with formation of a doublebond.

Particularly suitable are those compounds of the aetiocholane orpregnane series, unsaturated in the nucleus, which contain the namedsubstituent in ring and also contain in the positions 3, 7, 17, 20 or 21a free or substituted carbonyl, hydroxyl or carboxyl group. They may,apart from this, be of any steric configuration. The following compoundsmay, for example, be used: A -11- hydroxy pregnene-BzZO-diones, A-11:21-dihydroxy-pregnene-S :20-diones, A -11: 17 :21-trihydroxypregnene 3:20-diones, A -1121 d ydroxy pregnene 3:20 diones, li-ll-hydroxyandrostene 3:17 diones, A -l1-hydroxy-aetiocholenic acids.Instead of the compounds named, the corresponding derivatives, partly orcompletely substituted in the hydroxyl and/or acid groups, may be used,whereby the hydroxyl groups may, for example, be esterified withcarboxylic acids such as acetic, propionic or benzoic acid, by sulphonicacids, hydrohalic acids or xanthogenic acids, and the carboxyl groupsesterified with any alcohol or phenol, or otherwise substituted. Furtherutilizable starting products are, for example, such compounds of theaetiocholane series which are unsaturated in the nucleus and contain afree or esterified hydroxyl group in ring C in the ll-posltionof thecyclopentanopolyhydrophenanthrene skeleton, and which contain on thell-carbon atom, e. g. in addition to a free, esterified or etherifiedhydroxyl group, a hydrocarbon radical such as an alkyl, alkenyl, alkinylor alkylene group. Moreover enol derivatives of ketones such as the enolesters and enol ethers may be used. In this case the enol groupings aregenerally changed into keto groupings salts of iodine or carboxylicacids An esterified hydroxyl group can also be eliminatedwith alkalis,alkaline earths, carbonates, carb'oxylic acid salts, or organic basessuch as pyridine, dir'nethylaniline, etc., in addition to the compoundsmentioned above. Instead of, or in combination with the above namedcompounds, increased tempera! ture and/or reduced pressure maybe used...7 reaction may also be carried out, if deemed ad-5.

visable, in the presence of inert gases. Instead of eliminating thehydrogen halide directly from the hydrohalic acid ester, the halogen canbe replaced in the known Way by a quaternary ammonium radical and thisthen eliminated.

The elimination products contain a new double bond in ring C of thecyclopentanopolyhydrophenanthrene skeleton, whose position is not ab-jsolutely certain. Starting from, for example,

A -11-hydroxy 21 acyloxy pregnene 3:20-

- or in combination with the others.

bisulphates, formic acid, oxalic acid, acid anhydrides such as aceticanhydride or phosphorus If the elimination products contain freehydroxyl groups such as secondary nuclearhfydroxyl groups or a ketolgroup in the l'l-positionthey can be subsequently treated withesterifyingor etherifying agents. The etherificationqan'di 3 ticularlyalso the conversion intosaccharidede rivatives is also carried outby,alreadyknown; methods. The acid radicals whichlare introduced byiknownmethods may be "of 'jnorganicor orgarlic, for instance ofaliphatic,"cycloaliphatic, aliphatic aromatic, aromatic or heterocyclicchar acter, they may be substituted, saturated or unsaturated, or maypossess a straight or branched chain. If there have been usedesterifying agents which, apart from the ester forming group, containsalt forming groups, such as carboxylic, phenolic or amino groups, theobtained esters may be subsequently converted into the correspondingsalts, thus transforming them into water-soluble derivatives.Furthermore, the nuclear hydroxyl groups in the elimination products canbe converted into keto groups by oxidizing agents, e. g., with chromicacid in glacial acetic acid or with permanganate, with metals,

metallic oxides, metallic alcoholates or phenolates in the presence ofcarbonyl compounds (acetone,

cyclohexanone, etc). The double bonds present in the nucleus may betemporarily protected by the addition of halogen or halogen halide.

If the elimination products contain, however, nuclear keto groups, thelatter may be subsequently converted :by means of reduction agents intosecondary or tertiary carbinol groups, for example, catalytically (suchas by means of hydrogen activated with nickel), by means of aluminiumisopropylate and isopropyl alcohol, by means of alkali metal in thepresence of alcohols, or by means of compounds of the Grignard type.

The compounds obtained by the above process are therapeutically valuableproducts or may be converted into such.

The following examples illustrate the invention but are not to beregarded as limiting it in any way. The parts given are by weight:

Example 1 One part of A -l1:21-dihydroxy-pregnene-3:20"-dione-21-acetate ('corticosterone acetate, M. Pt. 14'7.5-148.5 C.)is boiled under reflux with 7.5 parts of a mixture of 80% v./v. glacialacetic acid and. V./V. concentrated aqueous hydrochloric acid. Theproduct of the reaction is evaporated down in vacuo and the residueallowed to stand for some time at room temperature with 4 parts ofacetic anhydride and 5 parts of absolute pyridine. The mixture is againevaporated down in vacuo and the residue dissolved in a mixture of etherand chloroform, washed with diluted hydrochloric acid, soda solution andwater, and dried over sodium sulphate. The product obtained from theether and chloroform solution is dissolved in 7.5 parts of benzene andpentane (1:1) and filtered over a column of parts aluminium oxide. Ondeveloping the chromatogram with benzene and pentane (1:1), acrystalline fraction is first obtained which forms, afterrecrystallization from ether, needles melting at 142 C. and having amolecular formula 0231 13004. This compound has presumably the followingconstitution:

LU of 4 On washing with absolute benzene a further fraction is obtainedwhich gives, after recrystallization from acetone and ether, prismaticcrystals melting at 1575-1585 C. They have the molecular formulaC23H30O4 and probably the following constitution:

OOCH2000CHI COCHzOCOCHa pound consists of the unchanged initial product,whereas the former is an isomer of it. By saponification of the abovementioned compounds the free hydroxy ketones can be obtained.

Instead of esterifying the product of the reaction with aceticanhydride, it can be converted into other esters or into ethers, e. g.,by means of propionylating agents or agents forming glucosides. Insteadof using the 3-keto compound, one may also start, for example, from thecorresponding M -3-hydroxy-21-acyloxy-compounds. In this case the A -andA -3-hydroxy- 21-acyloxy-pregnadiene-20-ones thus obtained can beconverted into the 3-keto compounds described above by oxidation with,for example, chromium trioxide in glacial acetic acid, after temporarilyprotecting the double bonds.

Instead of the A -11:ZI-dihydroXy-pregnene- 3:20-dione-21-acetate, the A-11-epi-21-dihydroxy pregnene 3:20 dione diacetate may be used asstarting material.

Example 2 One part of A -11-hydroxy-pregnene-3:20- dione(ll-hydroxy-progesterone, M. Pt. 187-188 C.) is boiled for a short timeunder reflux with 10 parts acetic anhydride and 0.4 parts 50% sulphuricacid, and a large quantity of water added to the reaction mixture. Afterdissolving in ether and chloroform, the same procedure is adopted as inExample 1. The fraction obtained with benzene and pentane gives, afterevaporation and recrystallization from a mixture of ether and pentame, acompound melting at 122 0., molecular formula C21H2a02, and probablyhaving the following constitution:

C Ha

absolute ether which has presumably the following constitution:

COCHa CH3 CH COOH:

The corresponding A and A -dienic acids can be obtained in a similar wayfrom A- 3-hydroxy or -acyloxy or A -3-keto-11-hydromraetio-chlolenicacid.

Example 3 One part of A -l1-hydroxy-androstene-3:1'7- dione (M. Pt. 225C.) is treated 'with 5 parts of a mixture of glacial acetic acid andconcentrated aqueous hydrochloric acid, as in Example 1, and theresulting solution completely evaporated. The residue is chromatographedover aluminium oxide, whereby two crystalline products with the samemolecular formula C19H22O2 can be separated oiT. They consist presumablyof A and A -androstadiene-3:17-dione with the following constitutions:

Analogous compounds of the aetiocholane series with a newly introduceddouble bond in ring C are also obtained by starting fromll-hydroxyandrostanes unsaturated in the nucleus which have on thell-carbon atom a hydrocarbon radical such as an alkyl, alkenyl, alkinylor alkylene group and/or a free esterified or etherified hydroxyl group.

What I claim is:

1. A compound having the following structural formula CH3 CH3 (kc u /C 001120 COCH:

6 2. A compound having the following structural formula 4. A compoundhaving the structural formula:

CH3 CH3 0 O CHaOacyl TADEUS REICHSTEIN.

